Editorials

Treating thyrotoxicosis in pregnant or potentially pregnant women

The risk to the fetus is very low 

Thyrotoxicosis affects up to 0.2% of pregnant women.¹ If left untreated it is associated with increased fetal mortality and morbidity.² Treatment is with antithyroid drugs such as propylthiouracil or carbimazole, with  blockers reserved for presurgical treatment and immediate control of severe thyrotoxic symptoms. Considerable concern exists, however, about the potential adverse fetal consequences of maternal antithyroid treatment, and sometimes conflicting or inappropriate advice is given. Women exposed to antithyroid drugs or radioiodine immediately before or in early pregnancy need accurate and timely information when deciding whether to proceed with the pregnancy.

There are two concerns about antithyroid drugs for thyrotoxicosis: that the drugs cause hypothyroidism in the fetus and that they have teratogenic effects. These drugs cross the placenta and can sometimes cause fetal hypothyroidism and goitre.³ The fetal thyroid begins to develop at 5-6 weeks' gestation, with follicles and colloid production at 10-12 weeks. Adverse effects on fetal thyroid function are thus unlikely unless treatment begins after 10 weeks' gestation.⁴ In two studies in which antithyroid therapy was used in moderate doses maternal and fetal outcomes were satisfactory, regardless of which antithyroid drug was used. ^{2 5} Close monitoring of thyroid function, roughly once a month, is important because the need for antithyroid treatment often declines through pregnancy, and in the mid-trimester it may occasionally be discontinued.

Recent studies have not suggested that antithyroid treatment has adverse consequences on thyroid size or function or subsequent physical or intellectual development, as occurs in congenital hypothyroidism.⁶ There is equivocal evidence suggesting that placental transfer of propylthiouracil may be less than that of carbimazole or methimazole⁷ so this drug may be the least likely to damage the fetal thyroid.

Although risks to the fetal thyroid from moderate doses of antithyroid drugs appear to be small, the use of higher doses of carbimazole in combination with thyroxine to prevent hypothyroidism should be avoided in pregnancy. There is high placental transfer of carbimazole⁷ but not thyroxine,⁸ putting the fetus at risk of intrauterine hypothyroidism, even if the mother is euthyroid. Also, fetal abnormalities are more common in the offspring of women receiving thyroxine and carbimazole (9.5%) than in those treated with carbimazole alone (4.1%).⁸

The second concern is that antithyroid drugs may have teratogenic effects. Several case reports described a scalp defect, aplasia cutis, in the infants of women taking carbimazole or methimazole.⁹ However, systematic research does not suggest a high risk of aplasia cutis from exposure to thionamides.¹⁰ In a recent study of 643 neonates born to mothers with Graves disease no cases of aplasia cutis occurred, congenital malformations were significantly commoner in the offspring of women with untreated thyrotoxicosis (3/50; 6%) than in those receiving methimazole (3/593; 0.5%).⁸

Radioiodine should not knowingly be given in pregnancy. Its administration before or during pregnancy raises several concerns. The first is the direct effect of radioiodine on the fetal thyroid. Since the fetal thyroid can concentrate iodine from about 10-12 weeks' gestation radioiodine administered later than this may cause ablation, resulting in fetal and neonatal hypothyroidism with potentially severe and irreversible consequences, including mental retardation.

The second concern is the potential genetic effect resulting from parental gonadal exposure; several studies have shown chromosomal damage after radioiodine. However, the increased risk of genetic abnormalities arising from such exposure (0.003%) is far less than the spontaneous risk of genetic abnormalities (0.8%). Studies in Japanese atomic bomb survivors and in the offspring of those treated with high doses of radioiodine for thyroid cancer have shown little evidence of genotoxicity.¹¹ Nevertheless, an interval of at least four months is normally advised between maternal radioiodine therapy and conception and some also apply this interval to a prospective father.

The risk from radioiodine of heritable disease or cancer has been estimated at 1 in 12 000 per mGy to the fetus.¹² In early pregnancy, although the risk of cancer induction is not zero, it is much lower than in later stages of pregnancy.¹² Inadvertent therapy with iodine-131 has been associated with a normal fetus when radioiodine was administered before the 10th week of gestation.¹³ The threshold doses for fetal death and fetal malformation are far greater than those used in normal treatment of thyrotoxicosis. If the irradiation occurs at 8-15 weeks then, even if there is no effect on the fetal thyroid, there is still a possible "no threshold" effect on mental function; however, the predicted loss would be 0.03 intelligence quotient points per mGy, which is unlikely to be clinically important.¹² If, however, the radioiodine was taken up by the fetal thyroid (after about 10-12 weeks) then the destruction of the fetal thyroid and subsequent hypothyroidism would result in a greater loss of mental function than that due to the direct radiation effect.¹⁴

The final area of concern relates to breast feeding since all antithyroid drugs, and iodine, are excreted in breast milk. The proportion of the adult dose consumed by a breastfed baby has been calculated to be about 0.07% for propylthiouracil, 0.5% for carbimazole, and 10% for methimazole, so propylthiouracil is recommended, although carbimazole can also be used safely. The mammary gland binds iodide avidly, especially during lactation, so if iodine-131 is required during lactation breast feeding should be stopped and contact with the baby reduced to limit the radiation to the child to 1 mSv (this may need up to 3 weeks of no close contact).¹⁵

The published evidence thus suggests that antithyroid treatment during early pregnancy carries an extremely small risk to the fetus. The risk is lower than is commonly perceived and less than that of untreated thyrotoxicosis.

M J O'Doherty, Consultant physician. 

Department of Nuclear Medicine, Guys and St Thomas' Hospital, London SE1 7EH (m.odoherty{at}umds.ac.uk)

P R McElhatton, Consultant teratologist. 
S H L Thomas, Consultant physician. 

National Teratology Information Service, Regional Drug and Therapeutics Centre, Wolfson Unit of Clinical Pharmacology, Newcastle NE2 4HH

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